1. Field of the Invention
The present invention relates to methods and compositions for modulating receptors in postsynaptic neurons of damaged or diseased retinas. The invention also related to methods for using the compositions set forth herein for treatment of diseases of hyperexcitability such as epilepsy.
2. Related Art
Retinal degenerative diseases such as age-related macular degeneration (ARMD) involve progressive dysfunction and deterioration of rod and cone photoreceptors (e.g., Jackson et al., 2002). There is evidence that photoreceptor loss can lead directly or indirectly to diminished function of proximal, i.e., post-photoreceptor, retinal neurons (e.g., Strettoi et al., 2003). However, in certain cases these proximal neurons appear largely to retain their capacity for neural signaling (Medeiros & Curcio, 2001; Varela et al., 2003; Marc et al., 2003; Strettoi et al., 2003; Cuenca et al., 2004); the retina's loss of visual function follows from the inability of deteriorating rods and cones to stimulate postsynaptic membrane receptor proteins of post-photoreceptor neurons. Recent research aimed at developing therapies for ARMD and related blinding diseases includes efforts based on photoreceptor rescue/replacement through genetic engineering, cell transplantation, and provision of growth factors and protective biochemical agents (La Vail et al., 1998; Hauswirth & Lewin, 2000; Acland et al., 2001; Gouras & Tanabe, 2003; Wang et al., 2004). However, these approaches have not yielded a robust and effective therapy for ARMD to date.
Thus, there is a need to achieve restoration of visual function resulting from ARMD and otherwise. Alternative possible treatment modalities include using a prosthetic device that electrically stimulates retinal neurons (Peachey & Chow, 1999; Humayun & de Juan, 1998; Rizzo et al., 2001; Zrenner, 2002; Margalit et al., 2002; Humayun et al., 2003) or focally delivers neurotransmitters within the retina (Iezzi et al., 2002; Gasperini et al., 2003; Peterman et al., 2003, 2004). Common to current designs of retinal prostheses is a macroscopic structure (i.e., dimensions in millimeters or greater) intended for implantation and interfacing with remaining healthy post-photoreceptor neurons. However, a major hurdle inherent in these approaches is the difficulty of achieving, with a macroscopic implanted device, microlocalization and specificity of neuronal stimulation, attributes that are recognized as critical for the retina's spatial resolution of visual stimuli.
In normal photoreception, visual signaling in rod and cone photoreceptors of the vertebrate retina begins with photoisomerization of the 11-cis retinal chromophore of visual pigment in the rod and cone outer segments. This photoisomerization event converts the retinal to the all-trans form and initiates activating conformational changes of the protein (opsin) moiety of the pigment. Pigment photoactivation in turn initiates a chain of biochemical reactions that generate an electrical response. These activating stages of phototransduction, and reactions including those that deactivate the pigment and downstream transduction intermediates, determine the peak amplitude and time course of the electrical response to light (Burns & Baylor, 2001; Arshaysky et al., 2002). Complete recovery of the transduction machinery after illumination, i.e., complete dark adaptation of the photoreceptor, requires the action of metabolic and transport reactions that remove the all-trans retinal chromophore from opsin and provide resynthesized 11-cis retinal that binds to opsin, thereby regenerating photosensitive pigment (Saari, 2000; McBee et al., 2001). The photoreceptor electrical response transiently down-regulates the release of L-glutamate neurotransmitter at chemical synapses formed with retinal horizontal and bipolar cells. Resulting changes in the activity of postsynaptic membrane receptors of the bipolar cells produce a bipolar cell electrical response, thereby conveying visual signals initiated in the photoreceptors to neurons of the inner retina (Dowling, 1987; Wu & Maple, 1998; Thoreson & Witkovsky, 1999; Nawy, 2000).
There is a need to develop further, more robust and effective methods for treating ARMD and other diseases of sight, which have significant negative effects on patient health and well-being, as well as negative economic consequences for individuals and society in general.